ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.499C>T (p.Arg167Trp) (rs5030820)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132159 SCV000187233 pathogenic Hereditary cancer-predisposing syndrome 2019-04-16 criteria provided, single submitter clinical testing The p.R167W pathogenic mutation (also known as c.499C>T), located in coding exon 3 of the VHL gene, results from a C to T substitution at nucleotide position 499. The arginine at codon 167 is replaced by tryptophan, an amino acid with dissimilar properties. The p.R167W mutation has been reported in multiple patients and families with von Hippel-Lindau (VHL) syndrome (Babinska A et al. Neuro Endocrinol. Lett. 2015 Dec;36:517-20; Vikkath N et al. Fam. Cancer. 2015 Dec;14:585-94; Lee JS et al. BMC Med. Genet. 2016 Jul;17:48; Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175(4):311-23; Chew WHW et al. Mol Genet Genomic Med. 2017 Sep;5(5):602-607) and is considered one of the most common mutations in the VHL gene. Available evidence suggests that germline mutations at codon 167 convey an increased risk for developing pheochromocytoma (Crossey PA et al. Hum. Mol. Genet. 1994 Aug;3:1303-8; Chen F et al. Hum. Mut. 1995;5:66-75; Zbar B et al. Hum. Mutat. 1996;8:348-57; Olschwang S et al. Hum. Mut. 1998;12:424-30; Fishbein L et al. Ann. Surg. Oncol. 2013 May;20:1444-50). In one study of sporadic versus hereditary pancreatic islet cell tumors (ICTs), ICTs were found in 7 of 15 individuals (47%) with this mutation. In contrast, ICTs were found in only 1% of individuals with the p.Y98H founder mutation, suggesting an increased risk for ICTs in carriers of the p.R167W mutation (Erlic Z et al. Endocr. Relat. Cancer. 2010 Oct;17:875-83). The p.R167W mutation has been shown in transfection assays to prevent elongin-mediated stabilization of the VHL protein (<span style="background-color:initial">Schoenfeld AR et al. Proc. Natl. Acad. Sci .USA. 2000 Jul;97:8507-12). Of note, this mutation is also designated as p.R238W (c.712C>T) in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation.
GeneDx RCV000213079 SCV000211816 pathogenic not provided 2018-07-03 criteria provided, single submitter clinical testing The R167W missense variant in the VHL gene has previously been reported in association with von Hippel-Lindau syndrome (VHL) (for examples, see Crossey et al., 1994; Matsuo et al., 2011; Zhang et al., 2015). Functional studies show R167W does not bind to elongin B or elongin C, resulting in an unstable protein that is rapidly degraded by the proteasome (Schoenfeld et al., 2000). The R167W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and occurs within the alpha domain and the elongin C binding region (Yuen et al., 2009). Furthermore, missense variants in the same residue (R167G, R167Q, R167L) have been reported in the Human Gene Mutation Database in association with von Hippel-Lindau syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on currently available evidence, we consider R167W to be pathogenic.
Invitae RCV000627746 SCV000285500 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-09-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 167 of the VHL protein (p.Arg167Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs5030820, ExAC 0.002%). This variant has been reported in individuals affected with von Hippel-Lindau syndrome and pheochromocytoma (PMID: 7987306, 12000816, 23512077, 19464396, 15300849). This variant has been reported to segregate with disease in families affected with von Hippel-Lindau syndrome (PMID: 25563310, 9829912). ClinVar contains an entry for this variant (Variation ID: 2218) Experimental studies have shown that VHL protein with this variant does not fully stabilize Jade-1, which is an important factor in renal tumor suppression (PMID: 14973063). Codon 167 is located in the alpha domain of the VHL protein and is reported to be important in maintaining protein structure. This codon is the most frequently mutated residue in the VHL gene, accounting for 46% of the mutations in patients with type 2 von Hippel-Lindau syndrome in one study (PMID: 22799452, 9829911). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000002302 SCV000697524 pathogenic Von Hippel-Lindau syndrome 2017-04-20 criteria provided, single submitter clinical testing Variant summary: The VHL c.499C>T (p.Arg167Trp) variant located in the alpha domain (via InterPro) involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome. This variant was found in 1/121114 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic VHL variant (0.0000208). Multiple publications have cited the variant in affected individuals ranging in phenotypes from VHL, renal carcinoma, hemangioblastoma and pheochromocytoma. Functional study, Schoenfield_2000, indicates the variant disrupts the elongin binding capability to VHL, a function that is essential for the tumor suppressor function of VHL. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
PreventionGenetics,PreventionGenetics RCV000213079 SCV000805354 pathogenic not provided 2018-03-12 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763092 SCV000893626 pathogenic Erythrocytosis, familial, 2; Pheochromocytoma; Von Hippel-Lindau syndrome; Renal cell carcinoma, nonpapillary 2018-10-31 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000002302 SCV001425320 pathogenic Von Hippel-Lindau syndrome 2020-05-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286650 SCV001473258 pathogenic none provided 2020-08-03 criteria provided, single submitter clinical testing The VHL c.499C>T; p.Arg167Trp variant (rs5030820), also reported as p.Arg238Trp, is a common pathogenic variant in individuals and families affected with Von Hippel-Lindau syndrome (Crossey 1994, Fishbein 2013, Peng 2017, Wang 2018, Zhang 2015). This variant is reported in ClinVar (Variation ID: 2218), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 167 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show loss of elongin binding leading to VHL protein degradation (Leonardi 2011, Ohh 1999, Peng 2017, Schoenfeld 2000). Additionally, other amino acid substitutions at this codon (Gln, Gly, Leu, Pro) have been reported in individuals with Von Hippel-Lindau syndrome and are considered pathogenic (Crossey 1994, Zhang 2015). Based on available information, this variant is considered to be pathogenic. References: Crossey PA et al. Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. Hum Mol Genet. 1994;3(8):1303-1308. Fishbein L et al. Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Ann Surg Oncol. 2013;20(5):1444-1450. Leonardi E et al. Identification and in silico analysis of novel von Hippel-Lindau (VHL) gene variants from a large population. Ann Hum Genet. 2011;75(4):483-496. Ohh M et al. Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel-Lindau protein. J Clin Invest. 1999;104(11):1583-1591. Peng S et al. Genotype-phenotype correlations in Chinese von Hippel-Lindau disease patients. Oncotarget. 2017;8(24):38456-38465. Schoenfeld AR et al. Elongin BC complex prevents degradation of von Hippel-Lindau tumor suppressor gene products. Proc Natl Acad Sci U S A. 2000;97(15):8507-8512. Wang Y et al. Pedigree analysis, diagnosis and treatment in Von Hippel-Lindau syndrome: A report of three cases. Oncol Lett. 2018;15(4):4882-4890. Zhang J et al. Clinical and genetic investigation of a multi-generational Chinese family afflicted with Von Hippel-Lindau disease. Chin Med J (Engl). 2015;128(1):32-38.
OMIM RCV000002302 SCV000022460 pathogenic Von Hippel-Lindau syndrome 2002-05-09 no assertion criteria provided literature only
OMIM RCV000002303 SCV000022461 pathogenic Pheochromocytoma 2002-05-09 no assertion criteria provided literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000002302 SCV000264764 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing
Database of Curated Mutations (DoCM) RCV000435817 SCV000504907 likely pathogenic Renal cell carcinoma, papillary, 1 2015-07-14 no assertion criteria provided literature only
Donald Williams Parsons Laboratory,Baylor College of Medicine RCV000002302 SCV000599963 pathogenic Von Hippel-Lindau syndrome 2015-06-02 no assertion criteria provided research This variant has been previously reported as disease-causing and was found twice in our study in patients with pheochromocytoma and family history of VHL.

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